This application is a 371 of PCT/EP96/02935 filed Jul. 1, 1996.
The invention relates to ring-shaped devices and to a method of manufacture the same.
The invention relates in particular to ring-shaped vaginal devices, i.e. to vaginal rings.
Ring-shaped devices, and especially vaginal rings, are well known in the art. A two-layered one-compartment vaginal ring, for example, is disclosed in U.S. Pat. No. 4,237,885, in which a drug (progestational or estrogenic steroid) on a carrier is encircled by a polymeric tube, consisting of an ethylene-vinylacetate copolymer, both ends of which are joined together with a solid polymeric plug. Devices of this type, however, do not provide acceptable release patterns. Improvement was sought by using other shapes or other materials. A two-layered one-compartment vaginal ring made from silicone elastomer has been disclosed in EP 0,050,867, which ring comprises a silicone elastomer core loaded with active substance surrounded by a non-loaded silicone elastomer layer, which consists of two different compositions. Another improvement was claimed in U.S. Pat. No. 4,292,965, which disclosed a three-layered one-compartment ring. This ring comprises an inert silicone elastomer core encircled by a medicated silicone layer, and a non-medicated silicone outer layer. These above-mentioned one-compartment rings have the disadvantage that, when loaded with more than one active substance, release patterns of these substances can not be adjusted independently. Such devices usually show sub-optimum release patterns for the different substances, whereas it is generally preferred that all substances are released in a controlled rate and during a similar duration of time. As a consequence the release ratio of the active substances undergoes a change after a period of time.
In an attempt to solve these problems a two-compartment vaginal ring has been disclosed in U.S. Pat. No. 4,596,576. This device comprises two two-layered compartments, each containing another active substance. An advantage of this device is that the release ratio can be changed by changing the lengths of the compartments. To achieve a suitable ring with a constant release ratio, it is however necessary to join the ends of the compartments by using inert stoppers, which completely prevent mixing of the active ingredients. One of the disadvantages of this device is the expensive and difficult method to join the compartment ends to the stoppers, which method can hardly be automated.
Apart from unfavourable release patterns, changing release ratios, and burst effects (excessive release in the first few days), which are frequently occurring with the known vaginal rings, most vaginal rings are prepared from silicone elastomer, which material is nowadays considered as less safe.
It is an objective of the present invention to provide a safe ring-shaped device, with a good release pattern, preventing the disadvantages of the known vaginal rings, and which can be manufactured in a simple automated manner. Another objective of the invention is to provide a ring-shaped device which, after introduction thereof into the vagina, releases the steroid hormones within a short time, preferably within one to two days, to reach the desired plasma levels.
It has been found that a ring-shaped device comprising:
(a) a first compartment comprising a non-medicated core of ethylene-vinylacetate copolymer, encircled by a steroid hormone loaded ethylene-vinylacetate copolymer middle layer, and a non-medicated outer layer of ethylene-vinylacetate copolymer;
(b) a second compartment comprising a core of ethylene-vinylacetate copolymer loaded with a steroid hormone and a non-medicated outer layer of ethylene-vinylacetate copolymer; and
(c) optionally placebo segments of a thermoplastic material separating the first from the second compartment, fulfils these requirements.
The ring-shaped device according to the invention, is preferably a vaginal ring which can be used for hormone replacement therapy (HRT) or contraception.
The ethylene-vinylacetate copolymer can be any commercially available ethylene-vinylacetate copolymer, for instance as available under the trade names Elvax(copyright), Evatane(copyright), Lupolen V(copyright), Movriton(copyright), Ultrathene(copyright), and Vestypar(copyright).
The thermo-plastic material of the placebo segments can be any thermo-plastic material suitable for pharmaceutical use, such as polypropylene; low, linear low, or very low density polyethylene; ethylene-vinylacetate copolymer, and, preferably, high density polyethylene, such as commercially available Alathon(copyright), Alkathene(copyright), Baylon V(copyright), Carlona(copyright), Carlona P(copyright), Dow PE(copyright), Eltex(copyright), Elvax(copyright), Evatane(copyright), Ferlene(copyright), Fortilene(copyright), Hi-fax(copyright), Hostaflex(copyright), Hostalen G(copyright), Hostalen PP(copyright), Lactene(copyright), Lupolen(copyright), Lupolen V(copyright), Lyton(copyright), Moplen(copyright), Movriton(copyright), Novatec(copyright), Novolen(copyright), Pro-fax(copyright), Propathene(copyright), Rigidex(copyright), Stamylan(copyright), Stamylan P(copyright), Stamylex(copyright), Teamex(copyright), Tenite(copyright), Trolen PP(copyright), Typar(copyright), Ultrathene(copyright), VestolenP(copyright), Vestypar(copyright), and Vestolen A(copyright).
Particularly good release patterns are obtained when the ethylene-vinylacetate copolymer middle layer of the first compartment is saturated with the progestogen and the ethylene-vinylacetate copolymer core of the second compartment is loaded with a just saturated, and most preferably with a sub-saturated mixture of the progestogen and the estrogen.
Preferred devices for contraceptive use have a first compartment wherein the steroid hormone is a progestogen and a second compartment wherein the steroid hormone is a mixture of a progestogen and an estrogen. Devices especially intended for HRT may advantageously have a first compartment loaded with a mixture of a progestogen and an estrogen and a second compartment loaded with a progestogen. The progestogens of the first and the second compartment may be the same or may be different.
Typically the ethylene-vinylacetate copolymer middle layer of the first compartment comprises the progestogen (or the mixture of the progestogen and the estrogen) in crystalline form.
The lengths of the compartments of the ring-shaped device are chosen to give the required performance. Ratios of the lengths of the first and second compartment are contemplated to be between 30:1 and 1:30, but usually are between 15:1 and 1:1, and preferably are about 2:1. The lengths of the placebo segments are long enough to prevent excessive mixing of the progestogen of the first compartment with the progestogen and/or estrogen of the second compartment. This is usually attained by applying placebo segments of a length between 0.5 and 70 mm. The necessary length depends on the nature of the thermo-plastic material and its capacity to prevent permeation of the active materials. Most ideally the placebo segment completely prevents mixing, since mixing disturbs the release pattern. In practice, however, some mixing, in particular after a longer period of time, occurs due to diffusion of the active ingredients through the placebo segment from one to the other compartment. Such mixing would ultimately lead to the same load of estrogen in both compartments, which of course is unwanted when the loads are meant to be different. Some minor mixing however, is not completely to be prevented and is allowed to the point that the mixing influences the release of the active ingredients in such a manner that plasma levels of active ingredients get outside the required values. In practice less than 10% mixing, and preferably less than 5% mixing one month after insertion of the device, is acceptable. Usually a length of the placebo segments being preferably about at least half of the length of the second compartment is sufficient to prevent excessive mixing.
The ring-shaped device can be manufactured in any size as required. In practice, however an outer ring diameter of about 53.5 mm, a cross sectional diameter of about 3.5 mm, a length of the first compartment of about 100 to 110 mm, a length of the second compartment of about 10 to 40 mm, and a length of each of the two placebo segments of about 5 to 20 mm, has been proven to be very suitable for all purposes. If no placebo segments are used the length of the first compartment is about 110 and the length of the second compartment is preferably 42-52 mm.
The progestogen can be any suitable progestogen, such as desogestrel, etonogestrel (3-ketodesogestrel), levonorgestrel, norgestrel, gestodene, and other compounds with similar progestogenic activity. Preferably the progestogen is etonogestrel. The estrogen can be any suitable estrogen, such as estradiol, estriol, mestranol, and ethinyl estradiol. For contraceptive use ethinyl estradiol is preferred, whereas for HRT estradiol is the preferred estrogen.
Using the most preferred ring-shaped device of the invention, the ethylene-vinylacetate copolymer layer of the first compartment is loaded with 5-60% w/w, and preferably with about 15% w/w of etonogestrel, and the ethylene-vinylacetate copolymer core of the second compartment is loaded with 0.05-3% w/w, and preferably about 0.25-0.5% w/w of etonogestrel and 0.05-5% w/w, and preferably about 0.75-1.5% w/w of ethinyl estradiol.
The preferred vaginal ring releases at least 90 xcexcg/day of etonogestrel and 10 xcexcg/day of ethinyl estradiol, with an upper limit of 450 xcexcg/day and 100 xcexcg/day respectively during Day 1-3, and 150 xcexcg/day and 20 xcexcg/day respectively during Day 4-21.
The ring-shaped devices can be prepared in any suitable manner for the manufacture of vaginal rings. A preferred method of manufacture of the ring-shaped device comprises co-extrusion of the core and the layer(s), medicated or non-medicated as required, of each of the first and second compartments to render a fibre with a medicated middle or core layer, respectively. These fibres are cut into pieces of the required lengths, and the pieces are assembled to the ring-shaped device in a mould kept at about 40xc2x0 C., by injection moulding with high density polyethylene of about 230xc2x0 C. The rings are thereafter packed in the usual manner.
Another method of manufacture is a welding technique, for instance the hot-gas welding technique, which is especially suitable when no placebo segments are used. This technique is well known in the art. Basically the hot-gas technique is performed in an apparatus consisting of two moulds which are used to clamp the fibre ends and hold them in line to each other. One mould is static and the other is movable. A movable stop is used to assure that the fibre ends are only sticking out of the mould by about 0.5 mm. The apparatus further comprises a capillary which is used to remove residual polymer. The capillary consists of two identical halves, one of which is mounted on the upper part of a mould and the other is mounted on the lower part of the mould. A hot-air gun is used to melt the fibre ends.
In another embodiment the two ethylene-vinylacetate copolymer fibres, loaded with either etonogestrel or a mixture of etonogestrel and ethinyl estradiol, are melt co-extruded together with the skin-core ethylene-vinylacetate copolymer to render a skin-core fibre. These skin-core fibres are cut into pieces of the required length and assembled to a ring in a mould with two suitable pieces injection moulded high density polyethylene and injection moulded at 230xc2x0 C., with a mould temperature of 40xc2x0 C. The rings are thereafter sterilised and packed in the usual manner, for instance packed in a sachet consisting of a PET (12 xcexcm)/aluminium (9 xcexcm)/LDPE (40 xcexcm) laminate.